ABCG1 is a novel ABC transporter that is present on macrophages and is a primary regulator of cholesterol efflux from macrophages to HDL in reverse cholesterol transport. Major unresolved questions in the field of atherosclerosis are whether ABCG1 directly regulates macrophage foam cell formation and thus, whether ABCG1 significantly influences atherosclerosis development. We have recently discovered in our laboratory that ABCG1 expression is dramatically downregulated in diabetic mouse macrophages, and that this ABCG1 downregulation decreases macrophage cholesterol efflux, thereby increasing foam cell formation in diabetic mice. Incidence of atherosclerosis is accelerated in patients with both type 1 and Type 2 diabetes 1"10. Recent work by Peter Edwards and colleagues showed that mice lacking ABCG1 had significant lipid deposition in multiple tissues, including both macrophages and endothelial cells11. Although atherosclerosis studies have not yet been performed in the ABCG1-deficient mice, the phenotypic profile of gross lipid accumulation in the animals strongly suggests that ABCG1 will be an important regulator of atherosclerosis development. In the current application, we hypothesize that chronic hyperglycemia in diabetes decreases macrophaqe ABCG1 function and results in increased macrophage foam cell formation in vivo. We hypothesize that the reduction in macrophage ABCG1 function increases atherosclerosis in the setting of diabetes. We propose to study how glucose regulates ABCG1 expression and function in diabetes.